Is S100B p.Ser19Pro (c.55T>C) pathogenic?

S100B p.Ser19Pro (c.55T>C) is classified Uncertain significance in S100B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.9352); Very rare (popmax 0.000254%, nfe).

How common is S100B p.Ser19Pro (c.55T>C) in the general population?

S100B p.Ser19Pro (c.55T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about S100B p.Ser19Pro (c.55T>C)?

AlphaMissense predicts likely pathogenic (score 0.9352) — an in-silico prediction, not a clinical call.

S100B p.Ser19Pro

c.55T>C · VCV4158575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9352	likely pathogenic · top 4% in S100B
REVEL	0.743	pathogenic-leaning
SaProt	LLR -13.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,049 bp · p 0.23 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,946 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,048 alleles · very rare exomes 3/1,461,802 · genomes 0/152,246 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: S100B
Protein: p.Ser19Pro
Coding: c.55T>C
MANE Select: NM_006272
Type: single nucleotide variant
Location: chr21:46602361 (GRCh38)
Gene constraint: LOEUF 1.494 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 91.08 · 15 PDB
Residue 19: the ef-hand 1 domain; an α-helix; a binding site

Full S100B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

S100B p.Asp13Asn Uncertain significance ★ ⚠ same type
S100B p.His91Arg Uncertain significance ★ ⚠ same type
S100B p.Ile12Thr Uncertain significance ★ ⚠ same type
S100B p.Leu36Phe Uncertain significance ★ ⚠ same type
S100B p.Leu45Ser Uncertain significance ★ ⚠ same type
S100B p.Leu4Pro Uncertain significance ★ ⚠ same type
S100B p.Phe74Tyr Uncertain significance ★ ⚠ same type
S100B p.Val53Leu Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/s100b-p-ser19pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown